Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([NH:9][C:10](=[O:23])[C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)=[N:13][CH:12]=2)[CH:5]=[CH:6][C:7]=1[CH3:8].[C@H:24]1([C:33](O)=[O:34])[CH2:29][CH2:28][C@H:27]([C:30]([OH:32])=[O:31])[CH2:26][CH2:25]1.CCN=C=NCCCN(C)C>CN(C=O)C>[I:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH2:18][CH2:19][N:20]([C:33]([CH:24]4[CH2:25][CH2:26][CH:27]([C:30]([OH:32])=[O:31])[CH2:28][CH2:29]4)=[O:34])[CH2:21][CH2:22]3)=[N:13][CH:12]=2)=[O:23])[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: O=C(O)[C@H]1CC[C@H](C(=O)O)CC1
Reactant: Cc1ccc(NC(=O)c2ccc(N3CCNCC3)nc2)cc1I
Agent: CCN=C=NCCCN(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(NC(=O)c2ccc(N3CCN(C(=O)C4CCC(C(=O)O)CC4)CC3)nc2)cc1I
Reaction time: 8 h
Yield: 12.4 %

Procedure:
A mixture of N-(3-iodo-4-methyl-phenyl)-6-piperazin-1-yl-nicotinamide (60 mg, 0.14 mmol), trans-1,4-cyclohexane dicarboxylic acid (122 mg, 0.71 mmol) in DMF (10 mL) was treated with EDCI (130 mg, 0.71 mmol). After stirring overnight the reaction mixture was partitioned between EtOAc and water. The water layer was made basic to pH 13 with solid NaOH. The EtOAc layer was removed and then the water layer was acidified to pH 5 with aq conc. HCl and extracted again with EtOAc. The EtOAc layer obtained after the latter extraction was dried over Na2SO4, filtered and concentrated to the product (10 mg, Yield: 12%). HRMS m/z calcd for C25H29N4O4I [M+H]+: 577.1306. Found: 577.1306.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[NH:8][CH:9]=[CH:10][C:3]=12.C(N(C(C)C)CC)(C)C.[CH2:20]([O:27][C:28]([N:30]([CH2:44][C@H:45]1[CH2:50][CH2:49][C@H:48]([C:51](Cl)=[O:52])[CH2:47][CH2:46]1)[C:31]([NH:33]C(OCC1C=CC=CC=1)=O)=[NH:32])=[O:29])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C[O-].[Na+]>C(#N)C.CO>[NH:8]1[C:4]2=[N:5][CH:6]=[CH:7][C:2]([NH:1][C:51]([C@H:48]3[CH2:47][CH2:46][C@H:45]([CH2:44][N:30]([C:28]([O:27][CH2:20][C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=4)=[O:29])[C:31]([NH2:33])=[NH:32])[CH2:50][CH2:49]3)=[O:52])=[C:3]2[CH:10]=[CH:9]1
Reactant: Nc1ccnc2[nH]ccc12
Reactant: N=C(NC(=O)OCc1ccccc1)N(C[C@H]1CC[C@H](C(=O)Cl)CC1)C(=O)OCc1ccccc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: N=C(N)N(C[C@H]1CC[C@H](C(=O)Nc2ccnc3[nH]ccc23)CC1)C(=O)OCc1ccccc1
Temperature: 40 °C

Procedure:
To a solution of 4-amino-1H-pyrrolo[2,3-b]pyridine (2.46 g) dissolved in acetonitrile (100 ml) was added diisopropylethylamine (6.5 ml). The mixture was stirred at 40° C. Trans-4-(1,3-dibenzyloxycarbonylguanidinomethyl)cyclohexanecarboxylic chloride (19.86 g) was added to this solution and the mixture was stirred at 50° C. for 2 hours. Then, diisopropylethylamine (6 ml) and trans-4-(1,3-dibenzyloxycarbonylguanidinomethyl)cyclohexanecarboxylic chloride (15.03 g) were added thereto and the mixture was stirred at 50° C. for 2 hours. The solvent was distilled away under reduced pressure and the residue obtained was dissolved in methanol (100 ml). Sodium methoxide (1.05 g) was added to this solution and the mixture was stirred under ice-cooling for 1 hour and at room temperature for 1 hour. The solvent was distilled away under reduced pressure, chloroform (200 ml) was added thereto and the mixture was washed with water. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 3.61 g of trans-N-(1H-pyrrolo[2,3-b]pyridin-4-yl)-4-(1-benzyloxycarbonylguanidinomethyl)cyclohexanecarboxamide, melting point 160°-162° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](I)=[C:6]([CH:11]=1)[CH2:7][NH:8][CH2:9][CH3:10].[CH:13]1([C:16](Cl)=[O:17])[CH2:15][CH2:14]1.C([O:21][C:22](=[O:41])[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[C:26](B2OC(C)(C)C(C)(C)O2)[CH:25]=1)C>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]2[C:27]([O:30][CH3:31])=[CH:26][CH:25]=[C:24]([CH2:23][C:22]([OH:41])=[O:21])[CH:29]=2)=[C:6]([CH2:7][N:8]([C:16]([CH:13]2[CH2:15][CH2:14]2)=[O:17])[CH2:9][CH3:10])[CH:11]=1
Reactant: CCNCc1cc(Br)ccc1I
Reactant: O=C(Cl)C1CC1
Reactant: CCOC(=O)Cc1ccc(OC)c(B2OC(C)(C)C(C)(C)O2)c1
Product: CCN(Cc1cc(Br)ccc1-c1cc(CC(=O)O)ccc1OC)C(=O)C1CC1

Procedure:
{4′-Bromo-2′-[(cyclopropanecarbonyl-ethyl-amino)-methyl]-6-methoxy-biphenyl-3-yl}-acetic acid (Compound 1-247) was prepared by following the procedures of Example 1 using the following materials: (5-bromo-2-iodo-benzyl)-ethyl-amine, cyclopropanecarbonyl chloride, and [4-methoxy-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-acetic acid ethyl ester.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([OH:8])[C:3]=1[C:9](=[O:11])[CH3:10].C(=O)([O-])[O-].[K+].[K+].[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.O>CC(C)=O>[CH2:18]([O:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([OH:8])[C:3]=1[C:9](=[O:11])[CH3:10])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CC(=O)c1c(O)cccc1O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: CC(=O)c1c(O)cccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 2′,6′-dihydroxyacetophenone (4 g) and potassium carbonate (3.82 g) in acetone (40 mL) was added benzyl bromide (3.13 mL), and the mixture was stirred at room temperature overnight. The reaction mixture was poured into water, and the precipitated crystals were collected by filtration. The crystals were washed with water and n-hexane, and dried under reduced pressure to give the title compound (3.67 g).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]2[N:19]([CH2:20][CH2:21]O)[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[N:12]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].C(N(CC)CC)C.CS(Cl)(=O)=O.O>C1COCC1>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:11]3=[N:12][C:13]4[C:14](=[N:15][CH:16]=[CH:17][CH:18]=4)[N:19]3[CH2:20][CH2:21]2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(Nc2nc3cccnc3n2CCO)cc1
Agent: CS(=O)(=O)Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(N2CCn3c2nc2cccnc23)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 82.2 %

Procedure:
To a solution of 2-{2-[(4-nitrophenyl)amino]-3H-imidazo[4,5-b]pyridin-3-yl}ethanol (2.2 g) and triethylamine (10 mL) in THF (100 mL) was added methanesulfonyl chloride (1.1 mL) at 0° C., and the mixture was stirred at 0° C. for 2 h. The mixture was poured into water and extracted with AcOEt. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. A mixture of the residue and potassium carbonate (3.1 g) in NMP (30 mL) was stirred at 100° C. overnight. After cooling to room temperature, the mixture was diluted with water. The formed crystals were collected by filtration to give the title compound (1.7 g).
Reaction SMILES: Cl.Cl.[C:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)([CH3:6])([CH3:5])[CH3:4].[Cl:19][C:20]1[N:25]=[CH:24][C:23]([C:26](Cl)=[O:27])=[CH:22][CH:21]=1.C(N(CC)CC)C.O1CCCC1>O>[C:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N:13]1[CH2:18][CH2:17][N:16]([C:26]([C:23]2[CH:24]=[N:25][C:20]([Cl:19])=[CH:21][CH:22]=2)=[O:27])[CH2:15][CH2:14]1)([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(C)(C)c1ccccc1N1CCNCC1
Reactant: O=C(Cl)c1ccc(Cl)nc1
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)c1ccccc1N1CCN(C(=O)c2ccc(Cl)nc2)CC1
Temperature: 25 °C

Procedure:
A mixture of 1-(2-tert-butylphenyl)piperazine dihydrochloride obtained in Reference Example 1 (0.5 g), 6-chloropyridine-3-carbonyl chloride (352 mg), triethylamine (0.835 mL), and tetrahydrofuran (30 mL) was stirred at room temperature for over-night. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by flash column chromatography (NH-silica gel, 0:100 hexane/ethyl acetate) to provide the title compound (635 mg, quant.) as a solid.
Reaction SMILES: [OH:1][CH:2]([CH3:20])[CH2:3][N:4]([CH2:16][CH:17]([OH:19])[CH3:18])[CH2:5][CH2:6][N:7](CC(O)C)[CH2:8][CH:9]([OH:11])[CH3:10].OCCN(CCO)CCN(CCO)CCO>>[OH:11][CH:9]([CH3:10])[CH2:8][NH:7][CH2:6][CH2:5][N:4]([CH2:16][CH:17]([OH:19])[CH3:18])[CH2:3][CH:2]([OH:1])[CH3:20]
Reactant: CC(O)CN(CCN(CC(C)O)CC(C)O)CC(C)O
Agent: OCCN(CCO)CCN(CCO)CCO
Product: CC(O)CNCCN(CC(C)O)CC(C)O

Procedure:
Examples of suitable hydroxyalkylated ethylenediamines include, but are not limited to N,N,N′,N′-tetrakis-(2-hydroxypropyl)ethylenediamine and N,N,N′,N′-tetrakis-(hydroxyethyl)ethylenediamine. N-hydroxyethyl, N,N′,N′-tris(2-hydroxypropyl)ethylenediamine, and combinations of two or more thereof will not give solid. Preferably the hydroxyalkylated ethylenediamine is N,N,N′,N′-tetrakis-(2-hydroxypropyl)ethylenediamine or N,N,N′,N′-tetrakis-(hydroxyethyl)ethylenediamine. The hydroxyalkylated ethylene diamine, N,N,N′,N′-tetrakis-(2-hydroxypropyl)ethylenediamine, is available commercially, for example, from BASF Corporation, Mount Olive, N.J., under the name QUADROL polyol.
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14](O)=[O:15])=[CH:11][CH:12]=2)[C@H:7]([O:17][C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)[CH2:6][C@@H:5]1[CH3:25])(=[O:3])[CH3:2].[NH3:26]>>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]([NH2:26])=[O:15])=[CH:11][CH:12]=2)[C@H:7]([O:17][C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)[CH2:6][C@@H:5]1[CH3:25])(=[O:3])[CH3:2]
Reactant: N
Reactant: CC(=O)N1c2ccc(C(=O)O)cc2[C@H](Oc2ccc(Cl)cc2)C[C@@H]1C
Product: CC(=O)N1c2ccc(C(N)=O)cc2[C@H](Oc2ccc(Cl)cc2)C[C@@H]1C

Procedure:
Reactions and treatments were carried out in the same manner as in Example 118, using 41.1 mg of (2S,4R)-1-acetyl-4-(4-chlorophenoxy)-2-methyl-1,2,3,4-tetra hydroquinoline-6-carboxylic acid instead of (2S,4R)-1-acetyl-2-methyl-4-(4-morpholinophenoxy)-1,2,3,4-tetrahydroquinoline-6-carboxylic acid, and using aqueous ammonia instead of monomethylamine. Thus, 58.5 mg (95.6%, cis-form only) of the title compound was obtained as a white crystalline powder.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[CH:9]=[N:10][N:11]([CH2:14]C2C=CC(C(OC)=O)=CC=2)[C:12]=1[NH2:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:26][O:27][C:28](=[O:38])[C:29]1[CH:34]=[CH:33][CH:32]=[C:31](CNN)[CH:30]=1>>[C:1]([O:5][C:6]([C:8]1[CH:9]=[N:10][N:11]([CH2:14][C:31]2[CH:32]=[CH:33][CH:34]=[C:29]([C:28]([O:27][CH3:26])=[O:38])[CH:30]=2)[C:12]=1[NH2:13])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)c1cccc(CNN)c1
Reactant: COC(=O)c1ccc(Cn2ncc(C(=O)OC(C)(C)C)c2N)cc1
Agent: Cl
Product: COC(=O)c1cccc(Cn2ncc(C(=O)OC(C)(C)C)c2N)c1

Procedure:
Compound prepared in an analogous manner to Intermediate #50, replacing 4-Hydrazinomethyl-benzoic acid methyl ester hydrochloride with 3-Hydrazinomethyl-benzoic acid methyl ester hydrochloride (Intermediate #53)
Reaction SMILES: [C:1]1([OH:11])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.Br[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15].C(=O)([O-])[O-].[K+].[K+]>C(O)C>[C:1]1([O:11][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)CBr
Reactant: Oc1cccc2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CCOC(=O)COc1cccc2ccccc12
Yield: 80 %

Procedure:
432 g 1-naphthol, 602 g ethyl 2-bromoacetate, 276 g potassium carbonate and 2.160 l. ethanol are refluxed for 18 hours, the precipitate filtered, the solvent evaporated under reduced pressure and the residue recrystallized from petroleum ether. The ester, which melts at 52° C., is obtained with an 80% yield.
Reaction SMILES: C(O[C:4]([C:6]1([CH2:12][CH2:13]OC)[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)=[O:5])C.[CH3:16][C:17]1[S:21][C:20]([S:22](Cl)(=[O:24])=[O:23])=[CH:19][CH:18]=1.[NH2:26][C:27]1[CH:32]=[CH:31][C:30]([O:33][S:34]([CH3:37])(=[O:36])=[O:35])=[CH:29][CH:28]=1>>[CH3:16][C:17]1[S:21][C:20]([S:22]([N:9]2[CH2:8][CH2:7][C:6]3([C:4](=[O:5])[N:26]([C:27]4[CH:32]=[CH:31][C:30]([O:33][S:34]([CH3:37])(=[O:36])=[O:35])=[CH:29][CH:28]=4)[CH2:13][CH2:12]3)[CH2:11][CH2:10]2)(=[O:24])=[O:23])=[CH:19][CH:18]=1
Reactant: CS(=O)(=O)Oc1ccc(N)cc1
Reactant: CCOC(=O)C1(CCOC)CCNCC1
Reactant: Cc1ccc(S(=O)(=O)Cl)s1
Product: Cc1ccc(S(=O)(=O)N2CCC3(CCN(c4ccc(OS(C)(=O)=O)cc4)C3=O)CC2)s1

Procedure:
Brown solid. MS (ESI): 485.08 (MH+). This example was prepared in analogy to example 1 step C) to D) from 4-(2-methoxy-ethyl)-piperidine-4-carboxylic acid ethyl ester (example 1 step B)), 5-methylthiophene-2-sulphonyl chloride and methanesulfonic acid 4-amino-phenyl ester.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:12][C@:11]([CH3:18])([CH:13]([O:16][CH3:17])[O:14][CH3:15])[C@@H:10]3[O:19][C@@H:9]3[C:8]=2[CH:20]=1)([O-:3])=[O:2].[OH:21][C:22]1[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][C:23]=1[NH:29][CH2:30][C:31]1[N:32]=[N:33][N:34]([CH3:36])[N:35]=1>>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:12][C@:11]([CH3:18])([CH:13]([O:16][CH3:17])[O:14][CH3:15])[C@H:10]([OH:19])[C@@H:9]([N:29]([C:23]3[CH:24]=[C:25]([CH3:28])[CH:26]=[CH:27][C:22]=3[OH:21])[CH2:30][C:31]3[N:32]=[N:33][N:34]([CH3:36])[N:35]=3)[C:8]=2[CH:20]=1)([O-:3])=[O:2]
Reactant: Cc1ccc(O)c(NCc2nnn(C)n2)c1
Reactant: COC(OC)[C@@]1(C)Oc2ccc([N+](=O)[O-])cc2[C@H]2O[C@H]21
Product: COC(OC)[C@@]1(C)Oc2ccc([N+](=O)[O-])cc2[C@H](N(Cc2nnn(C)n2)c2cc(C)ccc2O)[C@H]1O
Yield: 39 %

Procedure:
The same procedure as step 3 of example 1 was accomplished, except for using the epoxide compound (400 mg, 1.43 mmol) obtained in step 1 of example 2 and N-(2-hydroxy-5-methylphenyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amine. The crude product was purified by silica gel column chromatography (developing solvent-n-hexane:ethyl acetate=1:2), to give desired compound (280 mg, yield: 39%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([C:15]([O:17][CH3:18])=[O:16])=[CH:11][CH:10]=1.[C:19](Cl)(Cl)=[O:20].[CH:23]([N:26](CC)[CH:27](C)C)(C)C.CNC>ClCCl.C1(C)C=CC=CC=1.C1COCC1>[CH3:23][N:26]([CH3:27])[C:19]([NH:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([C:15]([O:17][CH3:18])=[O:16])=[CH:11][CH:10]=1)=[O:20]
Reactant: COC(=O)c1ccc(-c2ccc(F)cc2N)cc1
Reactant: CCN(C(C)C)C(C)C
Reactant: O=C(Cl)Cl
Agent: CNC
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: COC(=O)c1ccc(-c2ccc(F)cc2NC(=O)N(C)C)cc1
Reaction time: 16 h

Procedure:
A room temperature solution of Example 43A (100 mg, 0.41 mmol) in dichloromethane (2 mL) was treated with 1.9M phosgene in toluene (0.26 mL) and N,N-diisopropylethylamine (0.2 mL, 1.2 mmol), stirred for 16 hours, treated with 2M dimethylamine in THF (0.5 mL), stirred for 1 hour, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 50% ethyl acetate/hexanes to provide the desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:23]([O:25][CH3:26])=[O:24])[C:5]([CH3:22])=[C:6]([CH:21]=1)[O:7][CH:8]1[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH2:9]1.Cl.O1CCOCC1>C(Cl)Cl>[ClH:1].[Cl:1][C:2]1[CH:21]=[C:6]([O:7][CH:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[C:5]([CH3:22])=[C:4]([CH:3]=1)[C:23]([O:25][CH3:26])=[O:24]
Reactant: COC(=O)c1cc(Cl)cc(OC2CCN(C(=O)OC(C)(C)C)CC2)c1C
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: COC(=O)c1cc(Cl)cc(OC2CCNCC2)c1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 147.8 %

Procedure:
A solution of tert-butyl 4-(5-chloro-3-(methoxycarbonyl)-2-methylphenoxy)piperidine-1-carboxylate (300 mg, 0.782 mmol) in DCM (3 mL) was treated with 4 M HCl/dioxane (3908 μl, 15.63 mmol) and stirred for 1 h at RT. The slurry was filtered and dried to give methyl 5-chloro-2-methyl-3-(piperidin-4-yloxy)benzoate, hydrochloride (0.185 g, 0.578 mmol, 74% yield). 1H NMR (400 MHz, DMSO-d6) δ 1.76-1.94 (m, 2 H) 2.02-2.16 (m, 2 H) 2.30 (s, 3 H) 2.99-3.13 (m, 2 H) 3.16-3.26 (m, 2 H) 3.83 (s, 3 H) 4.78 (dt, J=6.95, 3.60 Hz, 1 H) 7.34 (d, J=2.02 Hz, 1 H) 7.40 (d, J=2.02 Hz, 1 H) 8.83 (br. s., 2 H). MS(ES) [M+H]+ 284.1.
Reaction SMILES: [C:1]1([CH2:7][C:8]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][CH:14]=[CH:13]3)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:20]([O:22][C:23]1[CH:24]=[C:25]([CH:28]=[C:29]([N+:32]([O-:34])=[O:33])[C:30]=1[OH:31])[CH:26]=O)[CH3:21].[NH2:35][C:36]([NH2:38])=[O:37].Cl>C(O)C>[CH2:20]([O:22][C:23]1[CH:24]=[C:25]([CH:26]2[C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[C:8]([C:10]3[CH:11]=[C:12]4[C:17](=[CH:18][CH:19]=3)[N:16]=[CH:15][CH:14]=[CH:13]4)[NH:38][C:36](=[O:37])[NH:35]2)[CH:28]=[C:29]([N+:32]([O-:34])=[O:33])[C:30]=1[OH:31])[CH3:21]
Reactant: O=C(Cc1ccccc1)c1ccc2ncccc2c1
Reactant: NC(N)=O
Reactant: CCOc1cc(C=O)cc([N+](=O)[O-])c1O
Agent: Cl
Solvent: CCO
Product: CCOc1cc(C2NC(=O)NC(c3ccc4ncccc4c3)=C2c2ccccc2)cc([N+](=O)[O-])c1O
Temperature: 25 °C
Yield: 9.3 %

Procedure:
To a solution of 2-phenyl-1-(quinolin-6-yl)ethanone (Intermediate 67) (100 mg, 0.4 mmol), 3-ethoxy-4-hydroxy-5-nitrobenzaldehyde (85 mg, 0.4 mmol) and urea (72 mg, 1.2 mmol) in 2 mL of ethanol was added 0.5 mL of conc. HCl and was stirred at reflux overnight. The mixture was cooled to room temperature and purified by preparative HPLC (20-50% acetonitrile+0.15% trifluoroacetic acid in water, over 15 min.), followed by column chromatography (PE:EtOAc=2:1-EtOAc:MeOH=10:1) to give Compound 132 (18 mg, yield 11.8%). 1H NMR (CD3OD 400 MHz): δ 8.84 (d, J=3.2 Hz, 1H), 8.30 (d, J=8.8 Hz, 1H), 7.94 (s, 1H), 7.86 (d, J=8.8 Hz, 1H), 7.66 (s, 1H), 7.59-7.52 (m, 2H), 7.19 (s, 1H), 7.06 (m, 3H), 6.95-6.94 (m, 2H), 5.45 (s, 1H), 4.13-4.05 (m, 2H), 1.41 (t, J=6.8 Hz, 3H); MS (ESI): m/z 483.3 [M+1]+.
Reaction SMILES: [CH3:1][O:2]C1C=CC2N=C(C3C=CC(N)=NC=3)SC=2C=1.[CH3:19][NH:20][C:21]1[N:26]=[CH:25][C:24]([C:27]2[S:28][C:29]3[CH:35]=[C:34](O)[CH:33]=[CH:32][C:30]=3[N:31]=2)=[CH:23][CH:22]=1>>[CH3:1][O:2][C:33]1[CH:34]=[CH:35][C:29]2[S:28][C:27]([C:24]3[CH:23]=[CH:22][C:21]([NH:20][CH3:19])=[N:26][CH:25]=3)=[N:31][C:30]=2[CH:32]=1
Reactant: CNc1ccc(-c2nc3ccc(O)cc3s2)cn1
Reactant: COc1ccc2nc(-c3ccc(N)nc3)sc2c1
Product: CNc1ccc(-c2nc3cc(OC)ccc3s2)cn1

Procedure:
5-(6-Methoxy-1,3-benzothiazol-2-yl)pyridin-2-amine (190 mg, 0.74 mmol) was exposed to the procedure used for the preparation of 2-[6-(methylamino)pyridin-3-yl]-1,3-benzothiazol-6-ol. After neutralization, the precipitate was filtered off and washed with water. The crude solid was slurred in hot EtOAc/MeOH 95:5 and filtered. The filtrate was concentrated under reduced pressure and the residue was subjected to flash chromatography (EtOAc/MeOH 95:5) to give a product that was chromatographed once more (DCM/MeOH 95:5) to yield the title compound (65 mg). 1H NMR δ 9.74 (s, 1H) 8.53 (d, 1H) 7.93 (dd, 1H) 7.73 (d, 1H) 7.35 (d, 1H) 6.93 (dd, 1H) 6.61 (br s, 2H) 6.55 (d, 1H); MS m/z (M+H) 244.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[C:5]2[N:10]=[C:9]([C:11]([OH:14])([CH3:13])[CH3:12])[S:8][C:6]=2[N:7]=1.C(=O)([O-])[O-].[Na+].[Na+].[C:27](#[N:29])[CH3:28]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:7][C:2]1[N:3]=[CH:4][C:28]([C:2]2[N:3]=[C:4]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)[C:5]3[N:10]=[C:9]([C:11]([OH:14])([CH3:13])[CH3:12])[S:8][C:6]=3[N:7]=2)=[CH:27][N:29]=1
Reactant: CC(C)(O)c1nc2c(N3CCOCC3)nc(Cl)nc2s1
Reactant: CC#N
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CC(C)(O)c1nc2c(N3CCOCC3)nc(-c3cnc(N)nc3)nc2s1

Procedure:
2-(5-Chloro-7-morpholinothiazolo[5,4-d]pyrimidin-2-yl)propan-2-ol, 5-pyrimidine-2-amine boronic acid 68 (1.2 eq), and trans-dichlorobis(triphenylphosphine)palladium(II) (0.1 eq) were slurried with equal parts 1M sodium carbonate aqueous solution (3 eq) and acetonitrile. The solution was microwaved at 130° C. for 15 minutes. The solution was evaporated to dryness and purified by reverse phase silica gel chromatography to give the product 130.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][F:9])[C:3]=1F.[NH2:11][C:12]1[CH:16]=[CH:15][N:14]([CH3:17])[N:13]=1.Cl[C:19]1[C:28]2[C:23](=[CH:24][CH:25]=[C:26]([OH:29])[CH:27]=2)[N:22]=[CH:21][N:20]=1>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][F:9])[C:3]=1[O:29][C:26]1[CH:27]=[C:28]2[C:23](=[CH:24][CH:25]=1)[N:22]=[CH:21][N:20]=[C:19]2[NH:11][C:12]1[CH:16]=[CH:15][N:14]([CH3:17])[N:13]=1
Reactant: Oc1ccc2ncnc(Cl)c2c1
Reactant: FCc1cccc(F)c1F
Reactant: Cn1ccc(N)n1
Product: Cn1ccc(Nc2ncnc3ccc(Oc4c(F)cccc4CF)cc23)n1

Procedure:
The compound of Example 130 was manufactured by the same method as in Example 95, by a similar method thereto or by a combination of such a method with a conventional method using 1,2-difluoro-3-(fluoromethyl)benzene, 3-amino-1-methyl-1H-pyrazole and 4-chloro-6-hydroxy-quinazoline.
Reaction SMILES: [OH:1][C:2]([C:4]([F:7])([F:6])[F:5])=[O:3].[F:8][C:9]1[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:10]=1[O:11][CH:12]1[CH2:17][CH2:16][N:15]([C:18]2[N:23]=[C:22]3[CH2:24][NH:25][CH2:26][CH2:27][C:21]3=[N:20][C:19]=2[NH:28][CH:29]([CH3:31])[CH3:30])[CH2:14][CH2:13]1.[C:37]([CH2:39][C:40](O)=[O:41])#[N:38].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CC(N(C)C)=O>[F:8][C:9]1[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:10]=1[O:11][CH:12]1[CH2:13][CH2:14][N:15]([C:18]2[N:23]=[C:22]3[CH2:24][N:25]([C:40](=[O:41])[CH2:39][C:37]#[N:38])[CH2:26][CH2:27][C:21]3=[N:20][C:19]=2[NH:28][CH:29]([CH3:31])[CH3:30])[CH2:16][CH2:17]1.[C:2]([OH:3])([C:4]([F:7])([F:6])[F:5])=[O:1]
Reactant: N#CCC(=O)O
Reactant: CC(C)Nc1nc2c(nc1N1CCC(Oc3ccc(F)cc3F)CC1)CNCC2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Solvent: O=C(O)C(F)(F)F
Product: CC(C)Nc1nc2c(nc1N1CCC(Oc3ccc(F)cc3F)CC1)CN(C(=O)CC#N)CC2
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 3-(4-(2,4-difluorophenoxyl)piperidin-1-yl)-N-isopropyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-amine TFA salt (42.8 mg, 0.070 mmol), cyanoacetic acid (9.0 mg, 0.105 mmol), HATU (40.0 mg, 0.105 mmol) in DMA was added DIPEA (36.7 μL, 0.211 mmol) at 23° C. The mixture was stirred at 60° C. for 30 min, cooled to 23° C., filtered, rinsed with DMSO, and purified by HPLC Method B, with the exception that a Waters XSelect® CSH C18, 5 μm, ID 4.6×50 mm was used, using an ACN gradient of 30% to 70% to give the title compound as a TFA salt (21.0 mg, 51.2%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6, mixture of rotamers) δ ppm 1.19 (d, J=6.6 Hz, 6H), 1.80-1.96 (m, 2H), 2.00-2.17 (m, 2H), 2.64 (t, J=5.6 Hz, 0.9H), 2.76 (t, J=5.7 Hz, 1.1H), 2.84-2.97 (m, 2H), 3.22-3.34 (m, 2H), 3.64 (t, J=5.8 Hz, 1.1H), 3.75 (t, J=5.9 Hz, 0.9H), 4.08-4.14 (m, 1H), 4.16 (s, 0.9H), 4.17 (s, 1.1H), 4.37 (s, 0.9H), 4.43 (s, 1.1H), 4.48-4.57 (m, 1H), 5.76 (br s, 1H), 6.98-7.06 (m, 1H), 7.24-7.36 (m, 2H); ESI-MS m/z [M+H]+ 471.5.